Antagonists of the muscarinic acetylcholine receptor M4
Inventors
Lindsley, Craig W. • Conn, P. Jeffrey • Engers, Darren W. • Engers, Julie L. • Temple, Kayla J. • Bender, Aaron M. • Baker, Logan A.
Assignees
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Publication Number
US-12577234-B2
Publication Date
2026-03-17
Expiration Date
Abstract
Disclosed herein are substituted hexahydro-1H-cyclopenta[c]pyrrole compounds, which may be useful as antagonists of the muscarinic acetylcholine receptor M4 (mAChR M4). Also disclosed herein are methods of making the compounds, pharmaceutical compositions comprising the compounds, and methods of treating disorders using the compounds and compositions.
Core Innovation
The disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, including related formula (Ia) and formula (Ib), with an arylene or a five- or six-membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from N, O, and S as A. The formula defines Q as selected from NR_a, O, and —NR_b—C(O)—, with m being 0, 1, or 2, and further specifies substituent variables R1, R2, R3, R4, R5, Y′, p, and independently selected ring substitution limits.
The disclosure identifies substituted hexahydro-1H-cyclopenta[c]pyrrole or cyclopenta[c]pyrrole derivatives, including stereochemically defined example compounds and substituted aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycle, and linked ring systems. The described compounds include pyridazinyl, pyrazolyl, pyridyl, thienyl, phenoxy, difluoromethoxy, tetrahydropyran-4-ylmethyl, morpholine, piperidyl, pyrrolidinyl, and related substituent classes within the stated structural framework.
The invention is described in connection with muscarinic acetylcholine receptor M4 (mAChR M4) antagonism, including pharmaceutical composition and method-of-use concepts. The compounds are directed to antagonizing mAChR M4 and treating neurodegenerative disorder(s) and movement/brain disorder(s), and includes background and biological assay content associated with mAChR M4 activity.
Claims Coverage
The consolidated claim coverage includes one broad independent compound claim and one independent treatment method claim. The compound claim defines a broad formula (I) chemical space with A, Q, m, R1-R5, Y′, p, and optional substitution limits, and the method claim covers treating a disorder by administering a therapeutically effective amount of the formula (I) compound to antagonize mAChR M4.
Formula (I) compound with defined arylene or heteroarylene A
A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein A is an arylene or a five- or six-membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from N, O, and S.
Q-linked core with variable m and substituent classes
Q is selected from NR_a, O, and —NR_b—C(O)—, with m being 0, 1, or 2, and the substituent groups R_a, R_b, R_c, R_d, R_e, R_f, and R_g being independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, and aryl, with R_c independently selected from hydrogen, C3-C6 cycloalkyl, and aryl.
R1, R2, and R3 substituent framework
R1 is selected from cycloalkyl, Br, —OR_c, —NR_dR_e, and —NHCOR_f; each R2 is independently selected from hydrogen, C1-C4 alkyl, halo, and —OR_g; and R3 is selected from hydrogen and C1-C4 alkyl.
R4 defined with Y′ ring selection and p range
R4 is selected from —(CR_hR_i)_p—Y′, hydrogen, C1-C8 alkyl, and C2-C8 alkenyl, where Y′ is selected from cycloalkyl, cycloalkenyl, heterocycle, aryl, and heteroaryl, each R_h and R_i is independently selected from hydrogen and C1-C4 alkyl, and p is 0, 1, 2, 3, or 4.
R5 classes and optional ring substitution
R5 is selected from hydrogen, C1-C4 alkyl, halo, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy, and each aryl, heteroaryl, arylene, heteroarylene, cycloalkyl, cycloalkenyl, and heterocycle is independently unsubstituted or substituted with 1-5 substituents.
Treatment by mAChR M4 antagonism
A method of treating a disorder in a subject who would benefit from antagonism of mAChR M4 by administering a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
Overall, the claims define a broad formula (I) compound family with explicit variable positions and substitution classes, together with a treatment method that uses the claimed compound to provide mAChR M4 antagonism.
Stated Advantages
Treating neurodegenerative disorder(s) and movement/brain disorder(s) by antagonizing mAChR M4.
A motor symptoms treatment method targeting Parkinson’s disease-related motor symptoms.
Documented Applications
Antagonizing mAChR M4 using the described compounds, including isotopically labeled compounds, within a pharmaceutical composition and method-of-use context.
Treating neurodegenerative disorder(s) and movement/brain disorder(s), including Parkinson’s disease, drug-induced Parkinsonism, dystonia, Tourette’s syndrome, dyskinesias, schizophrenia (including cognitive deficits associated with schizophrenia), excessive daytime sleepiness, ADHD, Huntington’s disease, chorea, cerebral palsy, and progressive supranuclear palsy.
Motor symptoms treatment method for Parkinson’s disease-related motor symptoms.
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